Cirrhosis is a chronic disease of the liver whose prevalence will dramatically increase during the next decade. Cirrhosis can result from a number of chronic liver diseases such as alcoholic liver disease, chronic viral hepatitis, non-alcoholic steatohepatitis, autoimmune diseases of the liver (primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis). Cirrhosis progresses over several years. The occurrence of complications indicates the transition to the phase called “decompensated” (approximately 100,000 patients per year in France); These complications include ascites (30,000 patients per year in France), gastrointestinal bleeding (10,000 episodes/year in France), renal failure and bacterial infections which is very common and often due to the translocation of Gram-negative intestinal bacteria.
Reactive oxygen species (ROS) produced by polymorphonuclear leukocytes (PMNs), monocytes or macrophages, termed respiratory burst (RB) or oxidative stress (OS), play a key role in antimicrobial host-defense systems. The enzyme responsible for the phagocyte RB, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), is a membrane multiprotein complex whose activation requires the phosphorylation and membrane translocation of cytosolic components, among which p47phox (phox: phagocyte oxidase) plays an important role. A deficient production of ROS promotes patients' susceptibility to microbial infections. Cirrhosis is a typical example in which inappropriate ROS production induces both tissue damage and patient susceptibility to infections. A common complication of cirrhosis is indeed the development of sepsis, a major cause of death, which is associated with impaired PMN RB, microbicidal activity, and phagocytosis. It was previously shown that neutrophils from patients with advanced alcoholic cirrhosis exhibited a severe deficient production of superoxide induced by the bacterial-derived peptide f-Met-Leu-Phe (fMLP) which was associated with impaired intracellular signaling (Rolas L et al, Hepatology, 2013). More particularly, it was recently disclosed that patient neutrophils were also deficient in Gp91phox expression determined by western-blot analyses (Rolas et al, 1st Meeting of the Neutrophil Club, Apr. 10, 2015, Paris). These data may explain in part the increased susceptibility of patients to bacterial infections and thus do not render credible use of TLR7/8 agonists for the treatment of bacterial infections in patients suffering from cirrhosis despite the fact that such compounds induce hyperactivation of the NADPH oxidase by stimulating the phosphorylation of p47phox on selective sites in healthy human neutrophils (Makni-Maalej et al. J. Immunol. 2012).